Aging and APOE genotype are two interacting risk factors for late onset Alzheimer's disease (AD). Oxidative stress is a major component of cellular aging. Lipid peroxidation, an important consequence of oxidative stress in brain, is attended by production of highly cytotoxic aldehydes that modify protein. The long term goal of this research project is to investigate mechanistic connections between aging and apoE metabolism in brain. The Specific Aims are to examine (1) the chemical mechanisms by which products of lipid peroxidation covalently modify relevant protein targets, such as apoE and tau, (2) the biological consequences of these reactions, and (3) the extent to which they correlate with severity of AD. The proposed research will employ a combination of organic chemistry to synthesize congeners of products of lipid peroxidation, and immunochemistry to follow their reactions. The Specific Aims will be examined in increasingly complex biological systems: neuroglial cell culture, hippocampal organotypic culture, and post mortem human brains with histopathologically verified diagnoses of AD.